Endotoxemia Explained

When the bowel's natural system of checks and balances is altered, the resulting endotoxin release can cause serious health issues

Although we'd like to think our horses are "sterile" on the inside, they are, in fact, harboring vats of micro-organisms within their intestinal tracts. In the normal, healthy bowel resident microbes limit the overgrowth of pathogenic bacteria. One type of microbial inhabitant, Gram-negative bacteria, which helps break down fibrous feed, releases a portion of its cell wall when it multiplies and then dies. What's released is called endotoxin.

Normally, bacteria or their components are restricted from traveling beyond the bowel's interior by a complex intestinal barrier; the bowel lining's mucosa (mucus-secreting membrane lining all body passages that communicate with the air) is made of epithelial cells that shield against endotoxin. Also, enzyme and antibody secretions block endotoxin passage. And when small amounts of endotoxin do make it through the mucosal barrier into the liver's circulation, specialized immune cells envelop and eliminate the toxin.

However, when the bowel's natural system of checks and balances is altered and microbial overgrowth leads to a die-off of Gram-negative bacteria, the resulting endotoxin release can cause serious health issues. "Problems develop when the intestinal barrier is injured, such as occurs with gastrointestinal disease or surgery, from reduced intestinal blood flow related to intestinal displacements," explains Anthony Blikslager, DVM, PhD, Dipl. ACVS, professor of equine surgery at North Carolina State University's College of Veterinary Medicine. "In addition, nonintestinal events such as septicemia (bacteria in the bloodstream) or post-foaling retained fetal membranes can cause large amounts of endotoxin to be absorbed into the central circulation." Bacterial, viral, or parasitic invasion might also alter gut flora and intestinal motility. And antibiotic therapy can change the gastrointestinal population, allowing overgrowth of some pathogenic bacteria strains.

Blikslager describes the earliest signs a horse owner might notice: "The horse seems to feel sick and the normally pink color of the mucous membranes becomes pale or 'injected' with redness or purplish color along the tooth line." He stresses that early recognition is key to a successful outcome--a recovered animal with no resulting damage.

Recognition

"Duration of the endotoxic crisis is the biggest issue, particularly with colic," says Blikslager. Medical treatments will provide only transient relief in severe cases, and a horse with pain that persists or recurs despite medicating with a mild sedative or painkiller should be transported immediately to a referral hospital for continued monitoring and medical therapy.

"The trick is to catch the problem as fast as possible and, when necessary, get the horse to surgery to quickly restore bowel function," he adds. Not only does prompt treatment help circumvent the inflammatory cascade, but it also starts the horse on the road to healing.

However, if the disruption of the intestine is purely inflammatory in nature (e.g., enteritis or colitis inflammatory conditions of the small or large intestine), medical therapy is indicated rather than surgery.

"It's rare to get a pure case of endotoxemia," observes Blikslager. "Usually there's some damage to the intestinal barrier with substances leaking into the circulation that set up conditions for systemic inflammatory response syndrome, or SIRS (the deterioration that occurs when the whole body is in an inflammatory state due to a bacterial infection)."

Respiratory Effects

Endotoxin in the environment can also cause damage, although not in the intestinal sense. Susan Holcombe, VMD, MS, PhD, Dipl. ACVS, ACVECC, an equine surgeon at Michigan State University's veterinary school, has examined environmental issues as factors in the development of inflammatory airway disease. These issues include ventilation, respirable particulates, endotoxin, and bedding and feed quality, among others.

"Gram-negative bacteria occur in high concentrations in horse manure, making endotoxin a component of barn dust, something that horses are exposed to daily," she explains. "Inhalation of dust and endotoxin induces airway inflammation and exacerbates heaves (also known as recurrent airway obstruction)." Holcombe stresses that horses stabled in a barn environment inhale as much as eight times more endotoxin than those living in pasture.

As a preventive measure, owners should remove horses from the barn while cleaning stalls and sweeping aisleways. In addition, owners can soak or steam hay to minimize endotoxin inhalation in horses at risk for heaves. However, wet hay should be fed immediately to prevent bacterial proliferation that could become a source of endotoxin as well.

Holcombe also points out that horses with severe sepsis and endotoxemia can develop lung inflammation and other pulmonary problems associated with edema (fluid swelling), as endotoxin induces these debilitating cardiopulmonary changes.

Commonly Used Treatments

As discussed, it's important to respond with medical treatment to help avert inflammation and to support the horse's cardiovascular system. Ideally, the veterinarian will help prevent endotoxin from entering the horse's circulation in the first place. "Unfortunately," Blikslager emphasizes, "All too often a horse isn't recognized as sick until clinical deterioration makes it obvious. Effective treatment relies on identifying and eliminating the underlying cause of illness."

The veterinarian's treatment goals are to neutralize the endotoxin, prevent it from binding to white blood cells, improve blood pressure, block additional release of inflammatory mediators, and prevent further adverse physiologic events. They might meet these with the following strategies:

Improve Blood Pressure Intravenous fluid therapy is a mainstay in treating a horse with excess endotoxin in the circulation. "Endotoxin dilates blood vessels, including those in the periphery," explains Blikslager, referring to the tiny vessels outside of the brain and heart. "This allows inappropriate deposition of blood in capillary beds, with not as much available centrally in the heart," visible as blood pooling in the aforementioned red, injected, or purple-colored mucous membranes.

"Although technically the horse may not be dehydrated, IV fluids increase the amount of circulating fluid volume in the heart to improve central venous pressure," he explains.

Hetastarch (a plasma substititute) is another material that pulls fluid into central blood vessels, particularly when given in conjunction with intravenous fluid therapy. Hypertonic saline acts in a similar way as hetastarch, but Blikslager notes that it also stimulates the vagus nerve (the longest of the cranial nerves, which extend from the brain) to increase cardiovascular function and, thus, improve blood pressure.

At one time veterinarians recommended the anticoagulant heparin to control coagulation factors that endotoxin adversely affects--in particular, the clotting of small vessels that might lead to laminitis, which continues to be a concern. "With the availability of new forms of heparin (low molecular weight heparin), recent scientific publications indicate that this can be an effective treatment," says Blikslager. "The problem remains early recognition of colic and laminitis."

Administer Non-Steroidal Anti-Inflammatory DrugsAnother method veterinarians use to address endotoxin's effects is to administer IV flunixin meglumine. "Flunixin is a mainstay therapy for colic and endotoxemia in horses, including its effect on reducing tumor necrosis factor, which is an important mediator of the inflammatory cascade," Holcombe notes.

Most NSAIDs work similarly to block pro-inflammatory enzymes (in this case, cyclooxygenase-1, or COX-1). Interestingly, Blikslager reports that European veterinarians prefer to manage endotoxemia with phenylbutazone (Bute), while in the U.S. they use flunixin ¬meglumine (Banamine).

"When initially available, flunixin meglumine was considered a miracle drug--horses looked better following treatment, at least externally; gum color improved; heart and respiratory rates subsided," Blikslager reports. "But we've come to realize that flunixin masks ongoing deterioration in approximately 5-10% of horses that have intestinal injury, such as from strangulation (twisted intestine)."

Holcombe stresses that flunixin can cause other negative effects, including gut and kidney toxicity.

"One important adverse event created by NSAIDs is that they slow intestinal repair," adds Blikslager. He notes that some forms of prostaglandin, while being inflammatory mediators, also have a ¬protective and reparative function for the intestinal lining--essentially, prostaglandis help cells crawl across the denuded areas. In normal intestinal tissue tight junctions between cells prevent substances from leaking out of the intestine and into the circulation. Prostaglandins are necessary to arrange these tight junction proteins. "If tight junctions remain open or are not repaired properly, then LPS continues to pass through and bind to immune surface cell receptors," explains Blikslager. "The result is continued release of inflammatory mediators."

Veterinarians often give horses lidocaine postoperatively to improve intestinal motility. While it has no direct effect on endotoxin, Blikslager reports it has a beneficial effect when given with NSAIDs: "Lidocaine can reverse flunixin-related inhibition of gut healing." Veterinarians administer the drug via specialized pumps that titrate (determine the concentration of a solution) the dose to their preference.

The new NSAID firocoxib is highly selective against COX-2 pro-inflammatory mediators (another type of degradative enzyme) and should have a role in reducing LPS-induced inflammation. However, Blikslager clarifies, "Use of a COX-2 inhibitor may not effectively manage pain (in these cases) and may decrease certain prostanoids (e.g., prostaglandins) that benefit gut repair." Meloxicam, a similar COX-2 inhibitor medication used in Europe, has a less adverse impact on the beneficial prostanoids, he notes, but high costs associated with obtaining FDA approval make it unlikely to become available in the United States.

Blikslager and colleagues are conducting clinical trials evaluating various NSAIDs and whether simple factors such as time of day for administration or breed of horse have any effect on the drugs' efficacy.

Bind EndotoxinVeterinarians have reported the value of low-dose intravenous administration of the antibiotic polymyxin B in binding endotoxin (and therefore preventing its interaction with white blood cells) but it must be given in a timely manner, before endotoxin crosses the intestinal barrier. Surgeons treating horses with intestinal twists often administer this drug before untwisting the bowel.

Some veterinarians might administer commercially available anti-endotoxin serum or plasma to sick horses to bind endotoxin. "Survivability is improved in horses, and particularly in foals, treated early on--those that are off feed or look like they aren't quite right," Blikslager remarks. The trick, however, is to get it on board before endotoxin circulates. He says, "Once endotoxin binds to surface cell receptors, inflammatory pathways are already turned on, and the effect of treatment is greatly reduced."

Diana Hassel, DVM, PhD, Dipl. ACVS, ACVECC, associate professor at Colorado State University's College of Veterinary Medicine & Biomedical Sciences, has experience using the intestinal protectant di-tri-octahedral (DTO) smectite (Bio-Sponge) in endotoxic horses. "Our studies ... show excellent efficacy in binding both clostridial toxins and endotoxin," she reports. "It's my initial treatment of choice and is most effective when administered early, at the first signs or suspicion of the development of diarrhea." She suggests that DTO-smectite shouldn't be used during an ileus (absence of bowel motility).

On the Horizon

Ethyl PyruvateHolcombe is investigating treating endotoxemic horses using a derivative of pyruvic acid called ethyl pyruvate that reportedly has antioxidative and anti-inflammatory properties.

"Identifying a clinically useful treatment for endotoxemia, without bad side effects, remains an important goal," she says. "Early treatment with ethyl pyruvate improves symptoms of whole body infection and shock in a variety of research animal models." In horse studies, she explains, "Sick endotoxic horses treated with ethyl pyruvate showed fewer colic symptoms and had improved clinical signs compared to those not receiving treatment. In addition, ethyl pyruvate blocked the production of blood-borne toxins."

PhenylmethimazoleHassel is currently performing pharmacokinetic and efficacy studies on a promising new drug, phenylmethimazole, for treating endotoxemia. "It may inhibit the activity of a cell surface receptor that plays a key role in propagating the negative effects of endotoxin," she reports. "Phenylmethimazole has shown tremendous promise in treating multiple conditions in other species, including sepsis, colitis, and pancreatic cancer. It appears to be quite safe for use in horses."

Because of endotoxemia's insidious nature, researchers are investigating many other existing pharmacological agents to combat its clinical effects, including:

Ketamine Researchers continue to investigate using low doses of the anesthetic ketamine as an anti-inflammatory medication. "Ketamine inhibits production of many toxins released into the blood during endotoxemia by blocking the site where endotoxin binds on blood cells," Holcombe reports.

Pentoxifylline Veterinarians have used this anti-inflammatory agent to treat horses with sepsis, endotoxemia, or laminitis. "Along with its immune-modulating properties, pentoxifylline has been reported to decrease production of toxic products in blood stimulated by endotoxin," says Holcombe. "¬However, there is little proven information that it helps horses with ¬endotoxemia.

Phospholipid Emulsion "Rapid (intravenous) infusion of a phospholipid emulsion demonstrated diminished effects of endotoxemia in horses," notes Holcombe. "However, beneficial results were offset by hemolysis (red blood cell contamination) problems ... so it is not yet available for clinical practice."

Cardiovascular support and stopping the inflammatory cascade as soon as possible are key to managing endotoxemia. The best treatment, however, is always one of prevention. For endotoxemia, that means helping the horse's gastrointestinal tract remain stable by avoiding abrupt feed changes, increasing the amount of fiber in the diet, and providing several small meals a day, rather than two large ones. Rapid recognition and resolution of any illness (gastrointestinal disease, colic, septicemia, or retained fetal membranes) that could potentially release endotoxin into the horse's circulation can also help prevent this condition.

About the Author

Nancy S. Loving, DVM, owns Loving Equine Clinic in Boulder, Colorado,
and has a special interest in managing the care of sport horses. Her book, All Horse Systems Go, is a comprehensive veterinary care and conditioning resource in full color that covers all facets of horse care. She has also authored the books Go the Distance as a resource for endurance horse owners, Conformation and Performance, and First Aid for Horse and Rider in addition to many veterinary articles for both horse owner and professional audiences.

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